September
24,
2021
(Drug DISCOVERY Specific Seminar)
Rational Development of Novel and Tight Inhibitors for Methyltransferases
Methyltransferases catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to their substrates. Methylation plays important roles in regulating signal transduction, chromatin reorganization, and gene transcription. Dysregulation of methyltransferases has been implicated in various diseases including cancer, neurodegenerative and cardiovascular diseases. Such critical cellular processes and dysfunction in which methyltransferases are implicated impose an urgent need for potent and selective inhibitors for each methyltransferase as chemical probes to delineate the roles under physiological and pathological conditions.
Guided by the Bi-Bi kinetic mechanism of methyltransferase, we have designed mechanism-based inhibitors to mimic its ternary complex by conjugating the substrate with a SAM analog. To illustrate the applications of this strategy, I will present a few examples in development of potent and selective inhibitors of protein N-terminal methyltransferase, protein arginine methyltransferase, and nicotinamide methyltransferase. These respective inhibitors displayed inhibitory activities at nM range and over 100-fold selectivity against a panel of methyltransferases. Kinetic analysis revealed the inhibition mechanism by competitively binding both SAM and substrate binding sties, which were further supported by the co-crystal structures in complex with the inhibitors. In summary, this mechanism-based strategy has the potential to be adapted to build potent and specific inhibitors for all methyltransferases.
Hosted by Weiping Tang
To obtain the Webex link for this seminar, contact Debra King at Debra.King@wisc.edu
